Estimating Post-treatment Recurrence After Multidrug-Resistant Tuberculosis Treatment Among Patients With and Without Human Immunodeficiency Virus: The Impact of Assumptions About Death and Missing Follow-up.

BACKGROUND: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment follow-up. METHODS: We analyzed data on 1991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using 5 approaches for handling post-treatment deaths, we estimated 6-month post-treatment TB recurrence risk overall and by HIV status. We used inverse-probability weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. RESULTS: The estimated TB recurrence risk was 7.4/1000 (95% credible interval: 3.3-12.8) when deaths were handled as non-recurrences and 7.6/1000 (3.3-13.0) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risks of composite recurrence outcomes were 25.5 (15.3-38.1), 11.7 (6.4-18.2), and 8.6 (4.1-14.4) per 1000 for recurrence or (1) any death, (2) death with unknown or TB-related cause, or (3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability weighting had a small impact on estimates. CONCLUSIONS: The estimated 6-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial.

RATIONALE: We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity. OBJECTIVES: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events. METHODS: We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure. MEASUREMENTS AND MAIN RESULTS: Each 5-mg/kg/d increase in rifampin dose resulted in differences of -0.011 (95% confidence interval, -0.025 to +0.002; P = 0.230) and -0.022 (95% confidence interval, -0.046 to -0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P = 0.011) but not with AUC0-6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%). CONCLUSIONS: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01408914) .

Accuracy of digital chest x-ray analysis with artificial intelligence software as a triage and screening tool in hospitalized patients being evaluated for tuberculosis in Lima, Peru.

Tuberculosis (TB) transmission in healthcare facilities is common in high-incidence countries. Yet, the optimal approach for identifying inpatients who may have TB is unclear. We evaluated the diagnostic accuracy of qXR (Qure.ai, India) computer-aided detection (CAD) software versions 3.0 and 4.0 (v3 and v4) as a triage and screening tool within the FAST (Find cases Actively, Separate safely, and Treat effectively) transmission control strategy. We prospectively enrolled two cohorts of patients admitted to a tertiary hospital in Lima, Peru: one group had cough or TB risk factors (triage) and the other did not report cough or TB risk factors (screening). We evaluated the sensitivity and specificity of qXR for the diagnosis of pulmonary TB using culture and Xpert as primary and secondary reference standards, including stratified analyses based on risk factors. In the triage cohort (n = 387), qXR v4 sensitivity was 0.91 (59/65, 95% CI 0.81-0.97) and specificity was 0.32 (103/322, 95% CI 0.27-0.37) using culture as reference standard. There was no difference in the area under the receiver-operating-characteristic curve (AUC) between qXR v3 and qXR v4 with either a culture or Xpert reference standard. In the screening cohort (n = 191), only one patient had a positive Xpert result, but specificity in this cohort was high (>90%). A high prevalence of radiographic lung abnormalities, most notably opacities (81%), consolidation (62%), or nodules (58%), was detected by qXR on digital CXR images from the triage cohort. qXR had high sensitivity but low specificity as a triage in hospitalized patients with cough or TB risk factors. Screening patients without cough or risk factors in this setting had a low diagnostic yield. These findings further support the need for population and setting-specific thresholds for CAD programs.

Accuracy of digital chest x-ray analysis with artificial intelligence software as a triage and screening tool in hospitalized patients being evaluated for tuberculosis in Lima, Peru.

Introduction: Tuberculosis (TB) transmission in healthcare facilities is common in high-incidence countries. Yet, the optimal approach for identifying inpatients who may have TB is unclear. We evaluated the diagnostic accuracy of qXR (Qure.ai, India) computer-aided detection (CAD) software versions 3.0 and 4.0 (v3 and v4) as a triage and screening tool within the FAST (Find cases Actively, Separate safely, and Treat effectively) transmission control strategy. Methods: We prospectively enrolled two cohorts of patients admitted to a tertiary hospital in Lima, Peru: one group had cough or TB risk factors (triage) and the other did not report cough or TB risk factors (screening). We evaluated the sensitivity and specificity of qXR for the diagnosis of pulmonary TB using culture and Xpert as primary and secondary reference standards, including stratified analyses based on risk factors. Results: In the triage cohort (n=387), qXR v4 sensitivity was 0.91 (59/65, 95% CI 0.81-0.97) and specificity was 0.32 (103/322, 95% CI 0.27-0.37) using culture as reference standard. There was no difference in the area under the receiver-operating-characteristic curve (AUC) between qXR v3 and qXR v4 with either a culture or Xpert reference standard. In the screening cohort (n=191), only one patient had a positive Xpert result, but specificity in this cohort was high (>90%). A high prevalence of radiographic lung abnormalities, most notably opacities (81%), consolidation (62%), or nodules (58%), was detected by qXR on digital CXR images from the triage cohort. Conclusions: qXR had high sensitivity but low specificity as a triage in hospitalized patients with cough or TB risk factors. Screening patients without cough or risk factors in this setting had a low diagnostic yield. These findings further support the need for population and setting-specific thresholds for CAD programs.

Estimating post-treatment recurrence after multidrug-resistant tuberculosis treatment among patients with and without HIV: the impact of assumptions about death and missing follow-up.

Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up. Methods: We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. Results: The estimated TB recurrence risk was 6.6 per 1000 (95% confidence interval (CI):3.2,11.2) when deaths were handled as non-recurrences, and 6.7 per 1000 (95% CI:2.8,12.2) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 24.2 (95% CI:14.1,37.0), 10.5 (95% CI:5.6,16.6), and 7.8 (95% CI:3.9,13.2) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small but apparent impact on estimates. Conclusion: The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

FAST tuberculosis transmission control strategy speeds the start of tuberculosis treatment at a general hospital in Lima, Peru.

OBJECTIVE: To evaluate the effect of the FAST (Find cases Actively, Separate safely, Treat effectively) strategy on time to tuberculosis diagnosis and treatment for patients at a general hospital in a tuberculosis-endemic setting. DESIGN: Prospective cohort study with historical controls. PARTICIPANTS: Patients diagnosed with pulmonary tuberculosis during hospitalization at Hospital Nacional Hipolito Unanue in Lima, Peru. METHODS: The FAST strategy was implemented from July 24, 2016, to December 31, 2019. We compared the proportion of patients with drug susceptibility testing and tuberculosis treatment during FAST to the 6-month period prior to FAST. Times to diagnosis and tuberculosis treatment were also compared using Kaplan-Meier plots and Cox regressions. RESULTS: We analyzed 75 patients diagnosed with pulmonary tuberculosis through FAST. The historical cohort comprised 76 patients. More FAST patients underwent drug susceptibility testing (98.7% vs 57.8%; OR, 53.8; P < .001), which led to the diagnosis of drug-resistant tuberculosis in 18 (24.3%) of 74 of the prospective cohort and 4 (9%) of 44 of the historical cohort (OR, 3.2; P = .03). Overall, 55 FAST patients (73.3%) started tuberculosis treatment during hospitalization compared to 39 (51.3%) controls (OR, 2.44; P = .012). FAST reduced the time from hospital admission to the start of TB treatment (HR, 2.11; 95% CI, 1.39-3.21; P < .001). CONCLUSIONS: Using the FAST strategy improved the diagnosis of drug-resistant tuberculosis and the likelihood and speed of starting treatment among patients with pulmonary tuberculosis at a general hospital in a tuberculosis-endemic setting. In these settings, the FAST strategy should be considered to reduce tuberculosis transmission while simultaneously improving the quality of care.

Development and Validation of a Food Frequency Questionnaire to Estimate Intake among Children and Adolescents in Urban Peru.

Tools to assess intake among children in Latin America are limited. We developed and assessed the reproducibility and validity of a semi-quantitative food frequency questionnaire (FFQ) administered to children, adolescents, and their caregivers in Lima, Peru. We conducted 24-h diet recalls (DRs) and focus groups to develop a locally-tailored FFQ prototype for children aged 0-14 years. To validate the FFQ, we administered two FFQs and three DRs to children and/or their caregivers (N = 120) over six months. We examined FFQ reproducibility by quartile agreement and Pearson correlation coefficients, and validity by quartile agreement and correlation with DRs. For reproducibility, quartile agreement ranged from 60-77% with correlations highest for vitamins A and C (0.31). Age-adjusted correlations for the mean DR and the second-administered FFQ were highest in the 0-7 age group, in which the majority of caregivers completed the FFQ on behalf of the child (total fat; 0.67) and in the 8-14 age group, in which both the child and caregiver completed the FFQ together (calcium, niacin; 0.54); correlations were <0.10 for most nutrients in the 8-14 age group in which the caregiver completed the FFQ on the child's behalf. The FFQ was reproducible and the first developed and validated to assess various nutrients in children and adolescents in Peru.

Nutritional Status and Tuberculosis Risk in Adult and Pediatric Household Contacts.

BACKGROUND: Studies show obesity decreases risk of tuberculosis (TB) disease. There is limited evidence on whether high body mass index also protects against TB infection; how very high body mass indices influence TB risk; or whether nutritional status predicts this risk in children. We assessed the impact of body mass index on incident TB infection and disease among adults and children. METHODS AND FINDINGS: We conducted a prospective cohort study among household contacts of pulmonary TB cases in Lima, Peru. We determined body mass index at baseline and followed participants for one year for TB infection and disease. We used Cox proportional regression analyses to estimate hazard ratios for incident TB infection and disease. We enrolled 14,044 household contacts, and among 6853 negative for TB infection and disease at baseline, 1787 (26.1%) became infected. A total of 406 contacts developed secondary TB disease during follow-up. Body mass index did not predict risk of TB infection but overweight household contacts had significantly decreased risk of TB disease (HR 0.48; 95% CI 0.37-0.64; p <0.001) compared to those with normal weight. Among adults, body mass index ≥ 35 kg/m2 continued to predict a lower risk of TB disease (HR 0.30; 95% CI 0.12-0.74; p 0.009). We found no association between high body mass index and TB infection or disease among children under 12 years of age. CONCLUSIONS: High body mass index protects adults against TB disease even at levels ≥ 35 kg/m2. This protective effect does not extend to TB infection and is not seen in children.

A cross sectional study of knowledge and attitudes towards tuberculosis amongst front-line tuberculosis personnel in high burden areas of Lima, Peru.

INTRODUCTION: Tuberculosis, reported as the second most common infectious cause of death worldwide, is a key mortality contributor in developing countries and globally. The disease is endemic in Peru and while relative success was achieved during the 1990s in its control, this slowed as new complications, such as multi drug resistant TB arose. Health centre workers participating in the national DOTS program, create the front-line TB work-force in Peru meaning their knowledge and attitudes about the disease are key in its control. METHODS: A Spanish language, multiple choice knowledge and attitudes survey was designed based on previous successful studies and the national Peruvian TB control guidelines. It was applied to two health networks in Lima, Peru amongst 301 health workers participating in the national TB control program from 66 different health centres. The study results were analysed to test mean knowledge scores amongst different groups, overall gaps in key areas of TB treatment and control knowledge, and attitudes towards the disease and the national TB control program. RESULTS: A mean knowledge score of 10.1 (+/- 1.7) out of 15 or 67.3% correct was shown. Demographics shown to have an effect on knowledge score were age and level of education. Major knowledge gaps were noted primarily in themes relating to treatment and diagnostics. Greater community involvement including better patient education about TB was seen as important in implementing the national TB control program. Participants were in disagreement about the current distribution of health resources throughout the study area. Discussion Serious knowledge gaps were identified from the survey; these reflect findings from a previous study in Lima and other studies from TB endemic areas throughout the world. Understanding these gaps and observations made by front-line TB workers in Lima may help to improve the national TB control program and other control efforts globally.